哥伦比亚大学Manu Ben-Johny小组在研究中取得进展。他们提出了一种肽调节剂的从头设计，以逆转与心律失常和癫痫相关的钠通道功能障碍。2025年8月18日出版的《细胞》杂志发表了这项成果。

以计算蛋白设计平台为主题，该团队设计了一种全新的肽调节剂，即通过失活门释放（ELIXIR）设计的迟电流抑制剂X，它以亚微摩尔亲和力结合Na_V通道。功能分析揭示了意想不到的抑制“致病性”I_NaL的选择性，并在细胞和小鼠模型中证实了其在逆转与心律失常和癫痫相关的Na_V功能障碍方面的有效性。这些发现证明了从头开始的蛋白质设计对工程合成离子通道调节剂的有效性，并为未来治疗方法的合理设计奠定了基础。

据悉，离子通道协调可兴奋细胞中的电信号。在自然界中，离子通道的功能是通过调节蛋白来实现的，这些调节蛋白已经进化到满足不同的生理需求。然而，精确调节离子通道功能的工程合成调制器具有挑战性。其中一个例子涉及启动动作电位的电压门控钠（Na_V）通道，其功能障碍放大了晚期/持续钠电流（I_NaL），这是多种人类疾病的共同基础，包括心律失常和癫痫。

附：英文原文

Title: De novo design of a peptide modulator to reverse sodium channel dysfunction linked to cardiac arrhythmias and epilepsy

Author: Ryan Mahling, Bence Hegyi, Erin R. Cullen, Timothy M. Cho, Aaron R. Rodriques, Lucile Fossier, Marc Yehya, Lin Yang, Bi-Xing Chen, Alexander N. Katchman, Nourdine Chakouri, Ruiping Ji, Elaine Y. Wan, Jared Kushner, Steven O. Marx, Sergey Ovchinnikov, Christopher D. Makinson, Donald M. Bers, Manu Ben-Johny

Issue&Volume: 2025-08-18

Abstract: Ion channels orchestrate electrical signaling in excitable cells. In nature, ion channel function is customized by modulatory proteins that have evolved to fulfill distinct physiological needs. Yet, engineering synthetic modulators that precisely tune ion channel function is challenging. One example involves the voltage-gated sodium (NaV) channel that initiates the action potential and whose dysfunction amplifies the late/persistent sodium current (INaL), a commonality that underlies various human diseases, including cardiac arrhythmias and epilepsy. Here, using a computational protein design platform, we engineered a de novo peptide modulator, engineered late-current inhibitor X by inactivation-gate release (ELIXIR), that binds NaV channels with submicromolar affinity. Functional analysis revealed unexpected selectivity in inhibiting “pathogenic” INaL and confirmed its effectiveness in reversing NaV dysfunction linked to both cardiac arrhythmias and epilepsy in cellular and murine models. These findings exemplify the efficacy of de novo protein design for engineering synthetic ion channel modulators and set the stage for the rational design of future therapeutic approaches.

DOI: 10.1016/j.cell.2025.07.038

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00860-8